CHOLESTEROL LEVEL LOWERING COMPOSITION

Description

Technical field.

[0001] The present application describes a composition containing as cholesterol lowering component, β-sitosterol and /or β-sitostanol, food containing such a composition, and a method to prepare the composition.

Background of the invention.

[0002] A daily intake of some compounds similar to cholesterol has been shown to have a cholesterol lowering effect. Specifically this is true for β-sitosterol and the hydrogenated form β-sitostanol (1-5).

[0003] Under β-sitosterol is also understood mixtures containing β-sitosterol, β-sitostanol and campesterol isolated from for instance soy or tall oil. Under β-sitostanol is also understood fully or partly hydrogenated β-sitosterol as above.

[0004] It is known that sterols and stanols are compounds with a very low solubility. They also crystallise easily. Several researchers have pointed at the importance that β-sitosterol and β-sitostanol must be adminstered in a formulation giving the optimal cholesterol lowering effect in the body. In a crystalline form even after efficient micronisation and/or in suspension the effect is lower than for solutions or emulsions (6-15). Hitherto described solutions and emulsions, however, have the disadvantage being too dilute to allow a simple intake in doses nescessary of about 1.5 g/day (16-18).

[0005] GB-A-1,365,661, relates to glycosides of sterols and in particular to a method for preparing a composition for medicinal or food purposes. The method encompasses the steps of dissolving β-sitosteryl-β-D-glucoside in a liquid medium and adding the resultant coposition in a monomolecularly dispersed state to a carrier selected from absorbent solids and emulsions. GB-A-1,365,661 does not relate to unmodified sterols as the present invention does.

[0006] It is thus not taught that the unmodified β-sitosterol is present in monomolecular form, but that a glucoside is present, which is contrary to the present invention.

[0007] EP-A-0 357 967 concerns β-sitosterol and/or β-sitostanol as such for treating cholesterolaemia with a content of phytosterols or their derivatives with improved water solubility. These compounds are present in an organic phase. However, this organic phase is not distributed, immobilised, and stabilized in a matrix. Besides the solubility of sterols in polyethylene glycols is about 2.5% at 20°C, which is far too low for achieving concentrations according to the present invention. The product thereof will result in a daily intake of 60 capsules of 1 g to reach the recommended dose.

[0008] DE-A-4,038,385 is concerned with microemulsions of sitosterol glucosides. Such microemulsions are distinguished by the fact that the concentrations of the participating components can vary only within very narrow, limited ranges. The microemulsions disclosed in the document are not edible and are toxic due to the presence of isopropanol.

[0009] JP-A-.62 126 966 is concerned with the problem of providing a composition of an instant powder (e.g., milk powder) with improved solubility and/or dispersability toward cold water. In order to improve the solubility, lecithin in combination with sterols or sterol derived compounds are added to the instant powder. The concentration of sterol is far too low for providing an cholesterol lowering effect in daily doses. Lecithin is used as a conventional surface active ingredient and not as a solvent. Accordingly the solution of JP-A-62 126 966 is not concerned with the same problem as the present invention.

[0010] WO 99/43218, which is a document according to Article 54(3)(4) EPC refers to a method for producing a fatty blend of plant sterol in a partly dissolved and for microcrystalline form.

[0011] The solubility in fat of sterols and stanols, both being alcohols, can be increased considerably by esterification with fatty acids. These esters are hydrolysed in the stomach and sterols and stanols are liberated as the initial alcohols in a concentration low enough not to allow recrystallisation. The cholesterol lowering effect in the gut is thus improved (16-20).

[0012] We have now shown that it is not necessary to esterify sterols and stanols to be able to distribute them in a sufficiently high concentration in a monomolecular, low associated or "cluster form" to reach necessary daily doses.

Description of the invention

[0013] The present invention is as set out in the claims.

[0014] In the present invention we show how the sterols and stanols by simple methods can be stabilised in monomolecular, low associated or "cluster" form by distributing and immobilising a solution of high concentration or a melt of sterols and/or stanols in a matrix.

[0015] The Sterols and/or stanols are initially dissolved in an organic phases; selected from mono- and/or , di glycerides, optionally in combination with lecithin at a temperature of 60° to 160°C. The solution is then mixed with a stabilising phase, matrix, containing a high molecular material e.g. gelatin, casein, starch syrup, pectin, ethylhydroxyethylcellulose or other at an elevated temperature. The mixture is then allowed to set to a solid, rubberlike or highly viscous mass. The stabilising phase can also be based on solvents being solid at room temperature.

[0016] The compositions as obtained by the claimed process can also be mixed into different food e.g. chocolate, dough/bread, jelly, mashed potatoes, butter/margarine, youghurt and others or be encapsulated or mixed into tablets.

[0017] The special characteristics of the present innovation are also shown by the enclosed claims.

[0018] The present innovation is described below by not limiting examples, If not otherwise stated the given values are in weight or weight %.

Example 1.

[0019] 30 g of β-sitostanol were dissolved in 70 g of a monoglyceride such as Dimodan RT at 90° C on a hot water bath and stirred till the stanol was completely dissolved. The 30% solution can be used directly or stored as a prefabricate after cooling as a homogenous mass.
20 g of the solution obtained were slowly added under intensive stirring to 80 g of a 35% solution of gelatin and agar 10:1 , starch syrop, sugar and aroma in water placed on a hot water bath at 65 °C.
The liquid highly viscous composition was immediately cast in small forms, where it solidified as a gel containing β-sitostanol in a stabilised monomolecular or low associated form.
The composition can be used as such or be mixed into food and/or be foamed, encapsulated or made into tablets.

Example 2.

[0020] 10 g of β-sitostanol were dissolved in 10 g of Dimodan RT at 120 °C on an oil bath. The solution was carefully under intensives stirring added to 80 g of a 30% solution of gelatin in water, also containing sugar and aroma, placed on a water bath of 85 °C. The homogenous stabilised composition was then treated as in example 1.

Reference Example 3.

[0021] 10 g of β-sitosterol were dissolved in 10 g of rapeseed oil at 120 °C on an oil bath. The solution was carefully under intensive continous stirring added to 30 g of a 30% solution of gelatin in water, containing sugar and aroma, placed on a hot water bath of 95 °C.
The homogenous stabilised composition was then treated as in example 1.

Reference Example 4.

[0022] 10 g of β-sitostanol were dissolved in 10 g of rapeseed oil at at 130 °C on an oil bath. The solution was carefully added under intensive continous stirring to 50 g of a 30% solution of gelatin in water, containing sugar and aroma, placed on a hot oil bath of 110°C.
The homogenised stabilised composition was then treated as in example 1.

Example 5.

[0023] 10 g of β-sitostanol were dissolved in 10 g of Dimodan RT at 120 °C on an oil bath. In another flask 80 g of chocolatemass were melted on the same bath. The 50% solution of β-sitostanol was slowly added under continous stirring to the chocolate. The composition was directly cast in forms, where it solidified and could be used as such or mixed into food or tableted, encapsulated or foamed.

Reference Example 6.

[0024] 10 g of β-sitostanol were dissolved in 10 g of rapeseed oil at 130 °C on an oil bath. In another flask 40 g of chocolatemass were melted at 110 °C on an oil bath. The 50% solution of β-sitostanol was added under continous stirring to the chocolate.
The composition was directly cast in forms where it solidified and can be used as such or mixed inte food or be tabletted, encapsulated or foamed.

Example 7.

[0025] 2.5 g of β-sitosterol were dissolved in 2.5 g of Dimodan ML at 80 °C. The solution was added to 1 litre of a 3% solution of sodium caseinate at 60-80 °C under strong stirring with a Turrax. After 5 minutes the emulsion was cooled to 20 °C and can be used as a beverage. The emulsion can be kept in a fridge during at least 3 days. The same result is obtained using milk.

Example 8.

[0026] 12.5 g of β-sitosterol were dissolved in 25 g of Dimodan ML at 60 °C. The solution was added to 80 g of melted margarine and mixed with 125 g of flour, 175 g of oatflakes, 2.5 g of baking powder and 80 g of sugar to a dough. The mixture was baked into 25 cakes of 18-20 g each containing 0.5 g of β-sitosterol.

REFERENSES

[0027] 

1 Pollak, O.J., Reduction of blood cholesterol in man. Cirkulation, 7, 702-706, (1953)

2 Grundy, S.M., Ahrens, E. H. Jr., and Davignon, J., The interaction of cholesterol absorption and cholesterol synthesis in man. J. Lipid Res., 10, 304,(1969).

3 Farguhar, J.W. .and Sokolow, M., Responce of serum lipids and lipoproteins of man to beta-sitosterol and sanflower oil - Along term study, Cirkulation, 17, 890,(1956).

4 Oster, P., Schlierf, G., Heuck, C.C., Greten, H.,Gundert-Remy, U., Haase, W. Klose, G., Nothelfer, A.,Raetzer, H., Schellenberg, B. und Schmidt-Gauk, H., Sitosterin bei familiären Hyperlipoproteinammie Tyo II. Eine randomisierte gekreuzte Doppelblindstudie, Dtsch, Med. Wschr., 101, 1308-1311, (1976).

5 Grundy, S.M., Mok, H.Y.I., Effekts of low dose phytosterols on cholesterol absorption in man, "Lipoprotein metabolism".,p114-118 ,Ed greten, H., Berlin, Heidelberg, New York,Springer-Verlag, (1976).

6 Miettinen, T.A., Siurala, M., Bile salts, sterols, sterol esters glycerides and fatty acids in micellar and oil phases of inerstinal contents during fat digestion in man, Z. Klin. Chem. Biochem., 9, 47-52, (1979)

7 Kudchodkar,B.J, Horlick, L., Sodhi, H,S. Effekts of plant sterols on cholesterol metabolism in man, Atherosclerosis, 23, 239 ,(1976).

8 Hassan, A.s., Rampone, A. J., Intestinal absorption and lymhatic transport of cholesterol and β-sitostanol in the rat, J. Lipid Res., 20, 646-653, (1979).

9 Heinemann, T., Kullak-Ublick, G.-K., Pietruck, B., von Bergman, K., Mechanisms of action of plants sterols on inhibition of cholesterol absorption, Eur. J. Clin. Pharmacol., 40 Suppl., 50-63,(1991).

10 Ikeda, I., Tanaka, K., Sugano, M., Vahouny, G.V., Gallo, I L,. Inhibition of cholesterol absorption in rats by plant sterols, J. Lipid Res., 29, 1573-1582, (1988)

11 Ikeda, I., Tanaka, K., Sugano, M., Vahouny, G.V., Gallo, I L,. Discrimination between cholesterol and sitosterol for absorption in rats, J. Lipid Res., 29,1583-1592, (1988)

12 Ikeda, I., Tanabe, Y and Sugano, M., Effects of sitosterol och sitotanol on micellar solubility of cholesterol, J. Nutr. Sci. Vitaminol., 35, 361-369, (1989).

13 Ikeda, I., Sugano, M., Comparison of absorption and metabolism of beta-sitosterol in rats, Atherosclerosis, 30, 227, (1978)

14 Sugano, M., Marioka, H. and Ikeda, I., A comparison of hypocholesterolemic activity of β-sitosterol och β-sitostanol in rats, J., Nutr., 107, 2011-2019,(1977).

15 Heinemann, T., Pietruck,B., Kullak-Ublick, G.-K., Pietruck, B., von Bergman, K.,Comparison of sitosterol and sitostanol on inhibition of intestinal cholesterol absorption,, Agents Action (Suppl), 26, 117-122, (1988).

16 Heinemann, T., Leiss, O., B., von Bergman, K., Effects of low-dose sitotanol onserum cholesterol in patients with hypercholesterolemia, Atherosclerosis, 61, 219-223, (1986).

17 Miettinen, T.A., Vanhanen,H., Dietary sitostanol related to absorbtion, syntesis and serum level of cholestol in different apolipoprotein e- phenotypes, Atherosclerosis, 105, 217-226, (1994).

18 Mattson, F.,H., Volpenstein, R.,A., Erickson, B.,A., Effects of plant sterol esters on the absorption of dietary cholesterol, J. Nutr., 107, 1139-1146 (1977)

19 Mattson, F.,H., Grundy, S.M., Crouse, J.R., Optimizing the effekt of plant sterols on cholesterol absorptionin man, Am. J. Clin. Nutr., 35, .697-700, /1982).

20 A substance for lowering high cholesterol level in serum and method for preparing the same. Patent C07J 9/00, A61K 31/575

Claims

1. A process for manufacturing a composition containing a cholesterol lowering component containing beta-sitosterol and/or beta-sitostanol in a monomolecular, low associated or cluster form, comprising

- melting or dissolving the beta-sitosterol and/or beta-sitostanol in an organic phase selected from mono, and diglycerides, and/or fatty acids, or mixtures thereof, optionally in combination with lecithin at a temperature of 60 to 160°C.

2. The process according to claim 1, wherein the temperature is in the interval of 60° to 150°C.

3. The process according to any one of the preceding claims, in which the matrix is based on a solid or highly viscous material such as gelatine, casein, pectin, agar, starch, starch syrup, ethyl hydroxyethyl cellulose, stearic acid, chocolate mass or a mixture of two or more of these.

4. The process according to any one of the preceding claims, in which the organic phase contains a monoglyceride.

5. The process according to any one of the preceding claims, wherein said matrix is based on a 10-50 wt-% solution of gelatine in water, and, if chosen, taste and aroma compounds.

6. The process according to any one of the preceding claims, in which the matrix at room temperature is a solid solvent such as stearic acid.

7. The process according to any one of the preceding claims, in which the cholesterol lowering agent is 1-99 wt-% of the organic phase.

8. Composition obtainable by a process according to any one of the preceding claims.

9. Food containing a composition as in claim 8, in an amount to ensure a cholesterol lowering effect.

10. Food as in claim 9 being butter, butter substitute, margarine, chocolate, jelly, bread, mashed potatoes, yogurt, soup.

11. Food as in claims 9-10, in which mentioned composition is included in the food in up to 60 wt-%.

12. Capsule, tablet, or foam containing a composition as in claim 8.

Ansprüche

1. Ein Prozess zur Herstellung einer Zusammensetzung, die eine cholesterinsenkende Komponent enthält, nämlich beta-Sitosterin und/oder beta-Sitostanol in einer monomolekylaren, schwach associierten oder "cluster" Form,
einschliesslich
schmelzen oder lösen von beta-Sitosterin und / oder beta-Sitostanol in eine organische Phase von Monoglyceriden, Diglyceriden und/oder Fettsäuren, wahlweise in Kombination mit Lecithin bei einer Temperatur von 60°C bis 160°C, und- bevor die Schmelze oder die Lösung kristallisiert oder in anderer Weise associiiert- es in ein Matrix verteilt wird so dass die erwähnte Komponente stabilisiert wird zum grössten Teil in monomolekularen oder schwach associierter oder "cluster" Form.

2. Ein Prozess wie in Anspruch 1, in dem die Temperatur im Intervall von 60°C bis 150°C liegt

3. Ein Prozess wie in einem der frueheren Ansprueche, wo die Matrix auf einem festen oder hoch viskoesen Material wie Gelatine, Kasein, Pectin, Stärke, Stärke Sirup,Ethylhydroxyethyl Zellulose, Stearinsäure, Schokolademasse oder einer Mischung von zwei oder mehr von diesen basiert.

4. Ein Prozess wie in einem der frueheren Ansprueche, wo die organische Phase ein Monoglycerid enthält.

5. Ein Prozess wie in einem der frueheren Ansprueche, wo die Matrix auf einer 10-50%-igen Lösung von Gelatine in Wasser basiert und wenn gewuenscht Geschmack und Aroma Verbindungen enthält.

6. Ein Prozess wie in einem der frueheren Ansprueche, wo die Matrix bei Zimmertemperatur ein festes Lösungsmittel wie Stearinsäure ist

7. Ein Prozess wie in einem der frueheren Ansprueche, wo die Komponent zur Senkung des Cholesterinspiegels ist 1-99% der organischen Phase beträgt.

8. Zusammensetung erhalten durch einen Prozess wie beschrieben in einem oder mehreren der frueheren Ansprueche.

9. Lebensmittel das die Zusammensetzung wie in Anspruch 8 in einer Menge enhält die den cholesterinsenkenden Effekt sicherstellt.

10. Lebensmittel wie in Anspruch 9 das Butter, Butterersatz, Margarine, Schokolade, Gelé,Brot, Kartoffelbrei, Yoghurt oder Suppe ist.

11. Lebensmittel wie in Ansprueche 9-10 in welchem die obenerwähnte Komposition in Mengen bis zu 60% vorhanden ist.

12. Kapsel, Tablett oder Schaum mit Zusammensetzung wie in Anspruch 8.

Revendications

1. Un procédé de préparation d'une mixture comprenant une substance, diminuant le taux de cholestérol, constituée de beta-sitosterol et/ou de beta-sitostanol sous une forme monomoléculaire, faiblement associée ou de cluster, consistant

- à faire fondre ou à dissoudre le beta-sitosterol et/ou le beta-sitostanol dans une phase organique choisie parmi des monoglycerides, des diglycerides et/ou des acides gras ou les deux, ou trois, associé (s) de façon facultative avec de la lécithine à une température comprise entre 60 et 160°C.

- et avant que le fondant ou la solution cristallise ou s'associe d'une certaine façon, le (ou la) répartir dans une matrice de telle façon que la substance mentionnée soit stabilisée principalement sous forme monomoléculaire, faiblement associée ou de cluster.

2. Le procédé selon la revendication 1, dans lequel la température élevée se situe dans un intervalle compris entre 60 et 150°C.

3. Le procédé selon la revendication 1 et 2, dans lequel la matrice est constituée d'un solide ou d'un matériau fortement visqueux tel que gélatine, caseine, pectine, agar, amidon, sirop d'amidon, cellulose éthylhydroxyéthyle, acide stéarique, masse de chocolat ou un mélange de deux ou de plusieurs de ces composés.

4. Le procédé selon l'une quelconque des revendications précédentes dans lequel la phase organique contient un monoglyceride.

5. Le procédé selon l'une quelconque des revendications précédentes, dans lequel la matrice est basée sur une solution aqueuse de gélatine à 10-50% et si choisi des composés pour le goût et l'arôme.

6. Le procédé selon l'une quelconque des revendications précédentes, dans lequel la matrice à température ambiante est un solvant solide tel que l'acide stéarique.

7. Le procédé selon l'une quelconque des revendications précédentes, dans lequel l'agent diminuant le taux de cholestérol représente 1 à 99% de la phase organique.

8. Mixture obtenue à partir d'un procédé selon l'une quelconque des revendications précédentes.

9. Aliment contenant une mixture telle que dans la revendication 8 dans une proportion pouvant assurer une diminution du cholestérol.

10. Aliment tel que dans la revendication 9 étant du beurre, des substitutifs du beurre, de la margarine, du chocolat, de la gelée, du pain, de la purée de pommes de terre, yoghourt ou soupe.

11. Aliment tel que dans la revendication 9-10 dans lequel le mélange mentionné est inclus dans l'aliment jusqu'à 60 %.

12. Capsule, tablette ou mousse contenant une composition telle que dans la revendication 8.